Is ITGA2B p.Leu830Arg (c.2489T>G) pathogenic?

ITGA2B p.Leu830Arg (c.2489T>G) is classified Uncertain significance in ITGA2B (ClinVar, Expert panel, 1 submitter; last evaluated 2025-04-15). AlphaMissense: likely pathogenic (0.9138); Very rare (popmax 0.0011%, sas); Associated with Glanzmann thrombasthenia.

What condition is associated with ITGA2B p.Leu830Arg (c.2489T>G)?

ITGA2B p.Leu830Arg (c.2489T>G) is associated with Glanzmann thrombasthenia (ClinVar).

How common is ITGA2B p.Leu830Arg (c.2489T>G) in the general population?

ITGA2B p.Leu830Arg (c.2489T>G) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Glanzmann thrombasthenia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ITGA2B p.Leu830Arg (c.2489T>G)?

AlphaMissense predicts likely pathogenic (score 0.9138) — an in-silico prediction, not a clinical call.

ITGA2B p.Leu830Arg

c.2489T>G · rs777802643 · VCV1879014

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9138 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Glanzmann thrombasthenia

ClinGen expert panel — Platelet Disorders VCEP

Uncertain Significance for Glanzmann thrombasthenia. Applied ACMG criteria (verbatim):

PM3_Supporting PM2_Supporting

Curation rationale (ClinGen, verbatim)

The NM_000419.5(ITGA2B):c.2489T>G (p.Leu830Arg) missense variant has been reported in at least one homozygous patient (UPN 9 in PMID: 16879215; PM3_supporting). The highest population minor allele frequency in gnomAD v4.1 is 0.00001098 (1/91048 alleles) in the South Asian genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PM3_supporting.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9138	likely pathogenic · top 7% in ITGA2B
REVEL	0.568	indeterminate
SaProt	LLR -17.15	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.23	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 13 kb · p 0.0004 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,048 alleles

Overall 6.84e-05% 1/1,461,818 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ITGA2B
Protein: p.Leu830Arg
Coding: c.2489T>G
MANE Select: NM_000419
dbSNP: rs777802643
Type: single nucleotide variant
Location: chr17:44375945 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.00 · 80 PDB
Residue 830: a β-strand

Full ITGA2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Glanzmann thrombasthenia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glanzmann thrombasthenia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ITGA2B c.1210+105A>G Likely pathogenic ★★★ same condition
ITGA2B c.1210+5G>A Likely pathogenic ★★★ same condition
ITGA2B c.1211-1G>C Likely pathogenic ★★★ same condition
ITGA2B c.1544+1G>A Pathogenic ★★★ same condition
ITGA2B c.1545-1G>A Pathogenic ★★★ same condition
ITGA2B c.1600+1G>A Pathogenic ★★★ same condition
ITGA2B c.1752+2T>C Pathogenic ★★★ same condition
ITGA2B c.1753-1G>A Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/itga2b-p-leu830arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown